Advanced prostate cancers disproportionally affect veteran populations in the US. One key feature of the advanced diseases is an aberrantly elevated cholesterol biosynthesis for the tumor, which likely contributes to the lethal progression of prostate cancer. However, the mechanisms underlying the aberration are poorly understood, which severely hinders exploitation of the unique metabolic vulnerability for effectively therapeutic intervention of advanced diseases. Epidemiological evidence from retrospective studies, including ones in the veterans populations, generally associate cholesterol-lowering drug statin use with improved survival and/or lower risk of advanced disease. However, thus far, clinical trials targeting advanced tumor cholesterol synthesis with statins have not yet yielded significant benefits to patients. Therefore, identification and elucidation of key factors that mediate the aberrant cholesterol biosynthesis in the advanced prostate cancers is urgently needed. This proposal is based on our recent discovery of a new therapeutic target, namely a nuclear receptor protein RORgamma, for prostate cancer and evidence of our further studies that suggest a possible direct role of the receptor protein and the cholesterol intermediates in promoting the aberrant cholesterol synthesis in the prostate cancer tumor cells. Our preliminary results also suggest that small-molecule inhibitors of the ROR can sensitize tumors to killing by statins. We therefor wish to establish the novel function of the ROR protein in control of the aberrant cholesterol synthesis in prostate cancer tumors, define its functional mechanisms and determine whether targeting the receptor protein with a potent, prostate cancer-selective, small-molecule inhibitor, in combination with statins, is a novel and highly efficacious therapeutic strategy for advanced prostate cancer.